U.S. patent number 6,427,682 [Application Number 09/483,096] was granted by the patent office on 2002-08-06 for methods and apparatus for aerosolizing a substance.
This patent grant is currently assigned to Aerogen, Inc.. Invention is credited to Yehuda Ivri, Mike Klimowicz.
United States Patent |
6,427,682 |
Klimowicz , et al. |
August 6, 2002 |
Methods and apparatus for aerosolizing a substance
Abstract
A device for aerosolizing a liquid includes a chamber having a
deformable wall which expands and contracts as fluid is delivered
and expelled from a fluid chamber. The chamber is partially bounded
by a vibrating structure having holes therein for expelling the
fluid. In another aspect, the invention provides exemplary
aerosolization apparatus and methods for aerosolizing a substance.
A liquid is transferred from a first chamber into a second chamber
having a substance that is in a dry state to form a solution. The
solution is then transferred from the second chamber and onto an
atomization member. The atomization member is operated to
aerosolize the solution.
Inventors: |
Klimowicz; Mike (Los Altos,
CA), Ivri; Yehuda (Irvine, CA) |
Assignee: |
Aerogen, Inc. (Sunnyvale,
CA)
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Family
ID: |
23918642 |
Appl.
No.: |
09/483,096 |
Filed: |
January 14, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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313914 |
May 18, 1999 |
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149426 |
Sep 8, 1998 |
6205999 |
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095737 |
Jun 11, 1998 |
6014970 |
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417311 |
Apr 5, 1995 |
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Current U.S.
Class: |
128/200.16;
128/200.14; 128/200.23 |
Current CPC
Class: |
A61M
11/005 (20130101); A61M 15/0065 (20130101); A61M
15/0085 (20130101); B05B 17/0646 (20130101); B05B
17/0676 (20130101); A61M 11/007 (20140204); A61M
15/025 (20140204); A61M 2016/0021 (20130101); A61M
2205/0233 (20130101); A61M 2205/3306 (20130101); A61M
2205/707 (20130101); A61M 2205/8206 (20130101) |
Current International
Class: |
A61M
15/00 (20060101); A61M 5/30 (20060101); B05B
17/04 (20060101); B05B 17/06 (20060101); B41J
2/025 (20060101); B41J 2/015 (20060101); B05B
12/08 (20060101); B05B 11/00 (20060101); C25D
1/08 (20060101); C25D 1/00 (20060101); A61M
16/00 (20060101); A61M 011/00 () |
Field of
Search: |
;128/200.14,200.16,200.23,200.24,203.12,203.15,207.14 |
References Cited
[Referenced By]
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Primary Examiner: Dawson; Glenn K.
Attorney, Agent or Firm: Townsend and Townsend and Crew
LLP
Parent Case Text
CROSS-REFERENCES TO RELATED APPLICATIONS
This application is a continuation in part application of U.S.
patent application Ser. No. 09/313,914, filed May 18, 1999, which
is a continuation in part of Ser. No. 09/149,426, filed Sep. 8,
1998, now U.S. Pat. No. 6,205,999 which is a continuation in part
of Ser. No. 09/095,737, filed Jun. 11, 1998, Now U.S. Pat.
6,014,970 which is a continuation in part of Ser. No. 08/417,311,
filed Apr. 5, 1995, the complete disclosures of which are herein
incorporated by reference.
Claims
What is claimed is:
1. A device for aerosolizing a liquid, comprising: a housing; a
vibrating structure having a front side, a back side and a
plurality of holes extending between the front and back sides, the
vibrating structure being mounted within the housing; means for
vibrating the vibrating structure; a container containing a fluid
and mounted within the housing; a chamber having a deformable wall
movable between a collapsed position and an expanded position, the
chamber being partially defined by the back side of the vibrating
element, the chamber receiving fluid from the container for
delivery through the plurality of holes in the vibrating element
upon vibration with the vibrating means.
2. The device of claim 1, wherein: the chamber moves to the
expanded position in response to fluid being delivered to the
chamber and moves to the collapsed position as fluid is expelled
through the plurality of holes.
3. The device of claim 1, wherein: the chamber contains a volume of
10-1000 .mu.L in the expanded position.
4. The device of claim 1, wherein: the chamber contains a volume of
less than 10 .mu.L when in the collapsed position.
5. The device of claim 1, further comprising: a valve positioned
between the container and the chamber, the valve preventing flow
from the chamber to the container.
6. The device of claim 5, wherein: the valve encloses part of the
chamber.
7. The device of claim 6, wherein: the valve is removably mounted
to the housing and is replaced together with the container.
8. The device of claim 1, wherein: the vibrating means is a
piezoelectric element coupled to the vibrating structure.
9. The device of claim 1, further comprising: a fluid outlet
positioned to deliver fluid from the container to the chamber, the
fluid outlet being positioned no more than 1 mm from the back side
of the vibrating structure.
10. The device of claim 1, wherein: the chamber contains the fluid
at a fluid pressure of less than 15 psi when in the expanded
position.
11. The device of claim 1, wherein: the chamber contains the fluid
at a fluid pressure of less than 5 psi when in the expanded
position.
12. The device of claim 1, wherein: the container has a piston
movable within a fluid cylinder containing the fluid, the piston
being movable within the cylinder to deliver a known quantity of
fluid to the chamber.
13. The device of claim 1, wherein: the container is removably
mounted to the housing for replacement with another container.
14. The device of claim 1, wherein: the wall is attached to the
container and is replaced when the container is replaced.
15. The device of claim 1, wherein: the wall has a portion which
generally conforms to a shape of the back side of the vibrating
structure when in the collapsed position.
16. The device of claim 1, wherein: the wall bows outward and away
from the vibrating structure when moving from the collapsed
position to the expanded position.
17. The device of claim 1, wherein: the wall is mounted to the
vibrating structure.
18. The device of claim 1, wherein: the vibrating structure
vibrates at a frequency of 120-150 kHz.
19. A method of aerosolizing a liquid, comprising the steps of:
providing a device for a zing a liquid, the device having a
housing, a vibrating structure, a container, and a fluid chamber,
the vibrating structure having a plurality of holes therein
extending between a front side and a back side, the container
containing a fluid and having a fluid outlet through which fluid is
expelled into the fluid chamber, the container being mounted within
the housing, the chamber being at least partially defined by a wall
and the back side of the vibrating structure, the chamber being
movable between a collapsed position and an expanded position;
delivering a desired quantity of fluid to the fluid chamber, the
delivering step being carried out with the chamber moving toward
the expanded position; and vibrating the vibrating structure to
expel the desired quantity of fluid from the fluid chamber, the
vibrating step expelling fluid which causes the wall to move toward
the collapsed position.
20. The method of claim 19, further comprising the step of:
removing and replacing the valve and the container with another
valve and container.
21. The method of claim 19, wherein: the delivering step is carried
out with a fluid pressure of less than 15 psi in the chamber.
22. The method of claim 19, further comprising the step of:
removing and replacing the wall.
23. The method of claim 22, wherein: the removing and replacing
step is carried out by also removing and replacing the
container.
24. The method of claim 19, wherein: the providing step is carried
out with a spring urging the wall against the vibrating structure
to seal the wall.
25. The method of claim 19, wherein: the providing step is carried
out with the wall attached to the container.
26. The method of claim 19, wherein: the providing step is carried
out with the wall having a portion which generally conforms to a
shape of the back side of the vibrating structure when in the
collapsed position.
27. The method of claim 19, wherein: the providing step is carried
out with the wall mounted to the vibrating structure.
28. The method of claim 19, wherein: the vibrating step is carried
out with the pressure in the chamber being less than a pressure at
the front side of the vibrating structure.
29. A method of aerosolizing a liquid, comprising the steps of:
providing a device for aerosolizing a liquid, the device having a
housing, a vibrating structure, a container, and a fluid chamber,
the vibrating structure having a plurality of holes therein
extending between a front side and a back side, the container
containing a fluid and having a fluid outlet through which fluid is
expelled into the fluid chamber, the container being mounted within
the housing, the chamber being at least partially defined by a wall
and the back side of the vibrating structure, the chamber being
movable from a collapsed position to an expanded position, the
chamber having a volume of 10-1000 .mu.L in the expanded condition;
delivering a desired quantity of fluid to the fluid chamber; and
vibrating the vibrating element to expel the desired quantity of
fluid from the fluid chamber.
30. The method of claim 29, wherein: the delivering step is carried
out with the chamber moving toward the expanded position; and the
vibrating step expels fluid which causes the wall to move toward
the collapsed position.
31. The method of claim 29, wherein: the providing step is carried
out with a valve positioned between the container and the chamber,
the valve preventing flow from the chamber to the container.
32. The method of claim 29, wherein: the delivering step is carried
out with a fluid pressure of less than 15 psi in the chamber.
33. The method of claim 29, further comprising the step of:
removing and replacing the wall.
34. The method of claim 33, wherein: the removing and replacing
step is carried out by also removing and replacing the
container.
35. The method of claim 29, wherein: the providing step is carried
out with a spring urging the wall against the vibrating structure
to seal the wall.
36. The method of claim 29, wherein: the providing step is carried
out with the wall attached to the container.
37. The method of claim 29, wherein: the providing step is carried
out with the wall having a portion which generally conforms to a
shape of the back side of the vibrating structure when in the
collapsed position.
38. The method of claim 29, wherein: the providing step is carried
out with the wall mounted to the vibrating structure.
39. The method of claim 29, wherein: the vibrating step is carried
out with the pressure in the chamber being less than a pressure at
the front side of the vibrating structure.
40. A method of aerosolizing a liquid, comprising the steps of:
providing a device for aerosolizing a liquid, the device having a
housing, a vibrating structure, a container, and a fluid chamber,
the vibrating structure having a plurality of holes therein
extending between a front side and a back side, the container
containing a fluid and having a fluid outlet through which fluid is
expelled into the fluid chamber, the container being mounted within
the housing, the chamber being at least partially defined by a wall
and the back side of the vibrating structure, the providing step
being carried out with a valve positioned between the container and
the chamber, the valve preventing flow from the chamber to the
container; delivering a desired quantity of fluid to the fluid
chamber; and vibrating the vibrating structure to expel the desired
quantity of fluid from the fluid chamber.
41. The method of claim 40, wherein: the delivering step is carried
out with the chamber moving toward a expanded position; and the
vibrating step expels fluid which causes the wall to move toward
collapsed position.
42. The method of claim 40, wherein: the providing step is carried
out with the chamber having a volume of 10-1000 .mu.L in the
expanded position.
43. The method of claim 40, wherein: the providing step is carried
out with the wall having a portion which generally conforms to a
shape of the back side of the vibrating structure when in the
collapsed position.
44. The method of claim 40, further comprising the step of:
removing and replacing the valve and the container with another
valve and container.
45. The method of claim 40, wherein: the delivering step is carried
out with a fluid pressure of less than 15 psi in the chamber.
46. The method of claim 40, further comprising the step of:
removing and replacing the wall.
47. The method of claim 40, wherein: the removing and replacing
step is carried out by also removing and replacing the
container.
48. The method of claim 40, wherein: the providing step is carried
out with a spring urging the wall against the vibrating structure
to seal the wall.
49. The method of claim 40, wherein: the providing step is carried
out with the wall attached to the container.
50. The method of claim 40, wherein: the providing step is carried
out with the wall mounted to the vibrating structure.
51. The method of claim 40, wherein: the vibrating step is carried
out with the pressure in the chamber being less than a pressure at
the front side of the vibrating structure.
52. A method of aerosolizing a liquid, comprising the steps of:
providing a device for aerosolizing a liquid, the device having a
housing, a vibrating structure, a container, and a chamber, the
vibrating structure having a plurality of holes therein extending
between a front side and a back side, the container containing a
fluid and having a fluid outlet through which fluid is expelled
into the fluid chamber, the container being mounted within the
housing, the chamber being at least partially defined by a wall and
the back side of the vibrating structure, the chamber being movable
from a collapsed position to an expanded position, the providing
step is carried out with a valve position between the container and
the chamber, thereby preventing flow from the chamber to the
container and the chamber having a volume of 10-1000 .mu.L in the
expanded position; delivering a desired quantity of fluid to the
fluid chamber; vibrating the vibrating element to expel the desired
quantity of fluid from the fluid chamber; and removing and
replacing the valve and the container with another valve and
container.
53. The method of claim 52, wherein: the delivering step is carried
out with the chamber moving toward the expanded position; and the
vibrating step expels fluid which causes the wall to move toward
the collapsed position.
54. The method of claim 52, wherein: the delivering step is carried
out with a fluid pressure of less than 15 psi in the chamber.
55. The method of claim 52, further comprising the step of:
removing and replacing the wall.
56. The method of claim 55, wherein: the removing and replacing
step is carried out by also removing and replacing the
container.
57. The method of claim 52, wherein: the providing step is carried
out with a spring urging the wall against the vibrating structure
to seal the wall.
58. The method of claim 52, wherein: the providing step is carried
out with the wall attached to the container.
59. The method of claim 52, wherein: the providing step is carried
out with the wall having a portion which generally conforms to a
shape of the back side of the vibrating structure when in the
collapsed position.
60. The method of claim 52, wherein: the providing step is carried
out with the wall mounted to the vibrating structure.
61. The method of claim 52, wherein: the vibrating step is carried
out with the pressure in the chamber being less than a pressure at
the front side of the vibrating structure.
62. A method of aerosolizing a liquid, comprising the steps of:
providing a device for aerosolizing a liquid, the device having a
housing, a vibrating structure, a container, and a chamber, the
vibrating structure having a plurality of holes therein extending
between a front side and a back side, the container containing a
fluid and having a fluid outlet through which fluid is expelled
into the fluid chamber, the container being mounted within the
housing, the chamber being at least partially defined by a wall and
the back side of the vibrating structure, a spring urging the wall
against the vibrating structure to seal the wall; delivering a
desired quantity of fluid to the fluid chamber; and vibrating the
vibrating element to expel the desired quantity of fluid from the
fluid chamber.
63. The method of claim 62, wherein: the delivering step is carried
out with the chamber moving toward an expanded position; and the
vibrating step expels fluid which causes the wall to move toward a
collapsed position.
64. The method of claim 62, wherein: the providing step is carried
out with the chamber having a volume of 10-1000 .mu.L in the
expanded position.
65. The method of claim 62, wherein: the providing step is carried
out with the wall having a portion which generally conforms to a
shape of the back side of the vibrating structure when in the
collapsed position.
66. The method of claim 62, wherein: the providing step is carried
out with a valve positioned between the container and the chamber,
the valve preventing flow from the chamber to the container.
67. The method of claim 62, further comprising the step of:
removing and replacing the valve and the container with another
valve and container.
68. The method of claim 62, wherein: the delivering step is carried
out with a fluid pressure of less than 15 psi in the chamber.
69. The method of claim 62, further comprising the step of:
removing and replacing the wall.
70. The method of claim 69, wherein: the removing and replacing
step is carried out by also removing and replacing the
container.
71. The method of claim 62, wherein: the providing step is carried
out with the wall attached to the container.
72. The method of claim 62, wherein: the providing step is carried
out with the wall mounted to the vibrating structure.
73. The method of claim 62, wherein: the vibrating step is carried
out with the pressure in the chamber being less than a pressure at
the front side of the vibrating structure.
74. A method of aerosolizing a liquid, comprising the steps of:
providing a device for aerosolizing a liquid, the device having a
housing, a vibrating structure, a container, and a chamber, the
vibrating structure having a plurality of holes therein extending
between a front side and a back side, the container containing a
fluid and having a fluid outlet through which fluid is expelled
into the fluid chamber, the container being mounted within the
housing, the chamber being at least partially defined by a wall and
the back side of the vibrating structure, the chamber having a
collapsed position, the providing step being carried out with the
wall having a portion which generally conforms to a shape of the
back side of the vibrating structure when in the collapsed
position; delivering a desired quantity of fluid to the fluid
chamber; and vibrating the vibrating element to expel the desired
quantity of fluid from the fluid chamber.
75. The method of claim 74, wherein: the delivering step is carried
out with the chamber moving toward a expanded position; and the
vibrating step expels fluid which causes the wall to move toward
the collapsed position.
76. The method of claim 74, wherein: the providing step is carried
out with the chamber having a volume of 10-1000 .mu.L in the
expanded position.
77. The method of claim 74, wherein: the providing step is carried
out with a valve positioned between the container and the chamber,
the valve preventing flow from the chamber to the container.
78. The method of claim 74, further comprising the step of:
removing and replacing the valve and the container with another
valve and container.
79. The method of claim 74, wherein: the delivering step is carried
out with a fluid pressure of less than 15 psi in the chamber.
80. The method of claim 74, further comprising the step of removing
and replacing the wall.
81. The method of claim 80, wherein: the removing and replacing
step is carried out by also removing and replacing the
container.
82. The method of claim 74, wherein: the providing step is carried
out with a spring urging the wall against the vibrating structure
to seal the wall.
83. The method of claim 74, wherein: the providing step is carried
out with the wall attached to the container.
84. The method of claim 74, wherein: the providing step is carried
out with the wall mounted to the vibrating structure.
85. The method of claim 74, wherein: the vibrating step is carried
out with the pressure in the chamber being less than a pressure at
the front side of the vibrating structure.
Description
BACKGROUND OF THE INVENTION
The invention relates generally to the field of inhalation drug
therapy, and in particular to the inhalation of aerosolized
chemical substances. In one aspect, the invention provides a
portable inhaler having a cartridge for storing a chemical
substance in a dry state and a liquid dispenser to introduce a
liquid to the substance to form a solution. Immediately after
formation of the solution, the inhaler aerosolizes the solution so
that it may be administered to a patient.
The atomization of liquid medicaments is becoming a promising way
to effectively deliver many medicaments to a patient. In particular
there is a potential for pulmonary delivery of protein peptides and
other biological entities. Many of these are easily degraded and
become inactive if kept in a liquid form. Proteins and peptides
often exhibit greater stability in the solid state. This results
primarily from two factors. First, the concentration of water, a
reactant in several protein degradation pathways, is reduced. See
Stability of Protein Pharmaceuticals, M. C. Manning, K. Patel, and
R. T. Borchardt, Pharm. Res. 6, 903-918 (1989), the complete
disclosure of which is herein incorporated by reference. Second,
the proteins and other excipients are immobilized in the solid
state. Water is a reactant in hydrolysis reactions, including
peptide change and cleavage, and deamidation. Reducing the water
concentration by freeze-drying or spray drying, reduces this
reactant concentration and therefore the rates of these degradation
pathways.
The mobility of the peptides or proteins, as well as other
molecules in the formulation, are reduced in the solid or dry
state. See Molecular Mobility of Amorphous Pharmaceutical Solids
Below Their Glass Transition Temperatures, B. C. Hancock, S. L.
Shamblin, and G. Zografi, Pharm. Res. 12, 799-806 (1995), the
complete disclosure of which is herein incorporated by reference.
For the peptides or proteins, this reduces the rate of
intermolecular interactions as well as intramolecular
conformational changes or fluctuations in conformation.
Minimization of intermolecular interactions will reduce protein and
peptide aggregation/precipitation, and will also reduce the rate of
diffusion of chemical reactants to the protein or peptide which
will slow the rate of chemical degradation pathways. Reduction in
intramolecular conformational changes reduces the rate at which
potentially reactive groups become available for chemical or
intermolecular interaction. The rate of this reaction may decrease
as the water concentration, and mobility of the protein, is
reduced.
One way to produce protein in solid or dry state is to transform
the liquid into a fine powder. When used for inhalation delivery,
such powders should be composed of small particles with a mean mass
diameter of 1 to 5 microns, with a tight particle size
distribution. However, this requirement increases the processing
and packaging cost of the dry powder. See also U.S. Pat. No.
5,654,007 entitled "Methods and System for Processing Dispersible
Fine Powders" and U.S. Pat. No. 5,458,135 entitled "Methods and
Devices for Delivering Aerosolized Medicaments", the disclosures of
which are incorporated herein by reference.
An easier way to transform a liquid solution to solid or dry form
is to use a freeze drying process where a liquid solution is
converted to a solid substance that can be readily reconstituted to
a liquid solution by dissolving it with a liquid, such as water.
Hence, one object of the present invention is to provide a way to
store a solid substance and combine the solid substance the with a
liquid to form a solution. Once the solution is formed, it is
another object of the invention to rapidly transport the solution
to an atomization device to allow the solution to be aerosolized
for administration. In this way, the solution is aerosolized
immediately after its reconstitution so that the degradation rate
of the substance is reduced.
A variety of nebulization devices are available for atomizing
liquid solutions. For example, one exemplary atomization apparatus
is described in U.S. Pat. No. 5,164,740, issued to Ivri ("the '740
patent"), the complete disclosure of which is herein incorporated
by reference. The '740 patent describes an apparatus which
comprises an ultrasonic transducer and an aperture plate attached
to the transducer. The aperture plate includes tapered apertures
which are employed to produce small liquid droplets. The transducer
vibrates the plate at relatively high frequencies so that when the
liquid is placed in contact with the rear surface of the aperture
plate and the plate is vibrated, liquid droplets will be ejected
through the apertures. The apparatus described in the '740 patent
has been instrumental in producing small liquid droplets without
the need for placing a fluidic chamber in contact with the aperture
plate, as in previously proposed designs. Instead, small volumes of
liquid can be placed on the rear surface of the aperture plate and
held to the rear surface by surface tension forces.
A modification of the '740 apparatus is described in U.S. Pat. No.
5,586,550 ("the '550 patent") and U.S. Pat. No. 5,758,637 ("the
'637 patent"), the complete disclosures of which are herein
incorporated by reference. These two references describe a liquid
droplet generator which is particularly useful in producing a high
flow of droplets in a narrow size distribution. As described in the
'550 patent, the use of a non-planar aperture plate is advantageous
in allowing more of the apertures to eject liquid droplets.
Furthermore, the liquid droplets may be formed within the range
from about 1 .mu.m to about 5 .mu.m so that the apparatus will be
useful for delivering drugs to the lungs.
Hence, it is a further objective of the invention to provide
devices and methods to facilitate the transfer of liquid solutions
(preferably those which have just been reconstituted) to such
aerosolizing apparatus so that the solution may be atomized for
inhalation. In so doing, one important consideration that should be
addressed is the delivery of the proper dosage. Hence, it is still
another object of the invention to ensure that the proper amount of
liquid medicament is transferred to an aerosol generator so that a
proper dosage may be delivered to the lungs.
In still another aspect of the present invention, the present
invention is directed to methods and devices for delivering fluids
to a vibrating element
SUMMARY OF THE INVENTION
The invention provides exemplary systems, apparatus and methods for
reconstituting a solid phase substance, e.g., a substance that is
in a dry state, with liquid to form a solution and for transporting
the solution to an aerosol generator for subsequent atomization. In
one exemplary embodiment, the system comprises a liquid dispenser,
a cartridge containing a substance in a dry state, and an aerosol
generator. In use, the cartridge is coupled to an outlet of the
dispenser and the dispenser is operated to dispense liquid from the
outlet and into the cartridge. The liquid then flows through the
substance and exits the cartridge as a solution.
In an exemplary aspect, the cartridge is replaced and disposed
after each use. After removal of the cartridge the user may
optionally operate the liquid dispenser to deliver liquid to the
aerosol generator for a subsequent cleaning cycle. In another
exemplary aspect, a liquid outlet of the cartridge is positioned
near the aerosol generator such that the solution is dispensed onto
the aerosol generator and is readily available for atomization.
The Liquid Dispenser
In an exemplary embodiment, the liquid dispenser comprises a
mechanical pump that is attached to a canister. The liquid
dispenser is disposed within a housing of the inhaler and is
configured to deliver a predetermined volume of liquid each time
the mechanical pump is operated. The dispensed liquid then flows
directly from the pump to the cartridge to form a solution which in
turn is deposited on the aerosol generator.
In one particular aspect, the liquid is a saline solution or
sterile water and may optionally contain an anti-microbial
additive. As previously mentioned, the solid substance in the
cartridge preferably comprises a chemical that is in the dry state
which is reconstituted into a solution upon introduction of the
liquid from the liquid dispenser.
In one particularly preferable aspect, the mechanical pump
comprises a piston pump that is connected to the canister. The
piston pump comprises a spring-loaded piston member that is
slidable within a cylindrical member which defines a metering
chamber. When the piston member is moved to a filling position, the
metering chamber is filled with liquid from the canister. When
released, the piston member moves to a dispensing position to
dispense a known volume of liquid from the metering chamber. In
this way, each time the pump is operated, a unit volume of liquid
is dispensed from the piston pump.
In one particularly preferable aspect, movement of the piston
member toward the filling position creates a vacuum inside the
cylindrical member that gradually increases until the piston member
reaches a point where a passage is provided between the piston
member and the cylindrical member. At this point, the piston member
has reached the filling position to allow liquid from the canister
to be drawn by the vacuum into the metering chamber of the
cylinder. At this point, the piston member is released and returns
by the force of the spring back to the dispensing position. During
the return travel of the piston member to the dispensing position,
the liquid in the metering chamber is displaced through an outlet
of the pump.
In another particular aspect, the piston pump is configured to
deliver volumes of liquid in the range of about 10 .mu.L to about
50 .mu.L each time the pump is operated. In another aspect, the
piston pump is configured such that it will dispense a full unit
volume only if the user fully depresses the piston to the filling
position. If the piston member is only partially depressed, no
liquid will be dispensed. In this manner, partial dosing is
prevented.
In still yet another aspect, the liquid dispenser further includes
a valve which serves to eliminate the dead volume in the piston
pump, thereby inhibiting microbial inflow into the liquid
dispenser. The valve preferably comprises a tubular valve seat that
is slidably disposed about a distal end of the piston member. In
this way, the liquid within the metering chamber moves the tubular
valve seat distally over the piston member to allow the liquid in
the metering chamber to be dispensed by flowing between the piston
member and the tubular valve seat when the piston member is moved
toward the dispensing position. The tubular valve seat is also
slidable within the cylindrical member, and the cylindrical member
defines a stop to stop distal movement of the tubular valve seat
relative to the piston member after the unit volume of liquid has
been dispensed from the metering chamber. Further, when the spring
forces the distal end of the piston member into a distal end of the
tubular valve seat, a seal is provided between the piston member
and the tubular valve seat to prevent microbial inflow into the
piston pump. Hence, use of the tubular valve seat in combination
with the piston member and the cylindrical member allows for a unit
volume of the liquid within the piston pump to be dispensed and
further provides a seal to prevent microbial inflow into the piston
pump.
The Drug Cartridge
The cartridge of the invention allows for the storage of a chemical
in a dry state. When a liquid is introduced into the cartridge, the
chemical substance dissolves within the liquid to form a solution
just prior to aerosolization of the solution.
In one exemplary embodiment, the cartridge comprises a housing
having an inlet opening and an outlet opening. Disposed in the
housing is a chemical substance which is in a dry state. As liquid
flows through the housing, the substance dissolves and flows
through the outlet opening as a solution. The chemical substance
may be any one of a variety of chemical substances, such as
proteins, peptides, small molecule chemical entities, genetic
materials, and other macromolecules and small molecules used as
pharmaceuticals. One particular substance is a lyophilized protein,
such as interferon alpha or alpha 1 prolastin. The lyophilized
substance is preferably held in a support structure to increase the
surface area that is in contact with the liquid, thereby increasing
the rate by which the substance is dissolved. The support structure
is preferably configured to hold the lyophilized substance in a
three-dimensional matrix so that the surface area of the substance
that is contact with the liquid is increased. Exemplary types of
support structures include open cell porous materials having many
tortuous flow paths which enhance mixing so that the solution
exiting from the outlet end is homogenized. Alternatively, the
support structure may be constructed of a woven synthetic material,
a metal screen, a stack of solid glass or plastic beads, and the
like.
When used in connection with the aerosolizing apparatus of the
invention, actuation of the liquid dispenser introduces liquid into
the inlet opening, through the support structure to dissolve the
substance, and out the outlet opening where it is disposed on the
aerosol generator as a solution. The aerosol generator is then
operated to aerosolize the solution. In this way, the substance is
stored in a solid state until ready for use. As previously
described, the flow of liquid from the liquid dispenser is produced
during the return stroke of the piston member, i.e. as the piston
member travels to the dispensing position. Since the return stroke
is controlled by the spring, it is not dependent on the user. In
this way, the flow rate is the same each time the liquid dispenser
is operated, thereby providing a way to consistently and repeatedly
reconstitute the solution.
In one particular aspect, the cartridge includes a coupling
mechanism at the inlet opening to couple the cartridge to the
liquid dispenser. In this way, the cartridge is configured to be
removable from the liquid dispenser so that it may be removed
following each use and discarded. In still another aspect, the
cartridge is filled with the chemical substance while in a liquid
state. The substance is then freeze dried and converted to a solid
state while in the cartridge.
The Aerosol Generator
In an exemplary embodiment, the aerosol generator that is employed
to aerosolize the solution from the cartridge is constructed in a
manner similar to that described in U.S. Pat. Nos. 5,586,550 and
5,758,637, previously incorporated herein by reference. In brief,
the aerosol generator comprises a vibratable member having a front
surface, a rear surface, and a plurality of apertures which extend
between the two surfaces. The apertures are preferably tapered as
described in U.S. Pat. No. 5,164,740, previously incorporated
herein by reference. In one particular aspect, the vibratable
member is preferably hemispherical in shape, with the tapered
apertures extending from the concave surface to the convex surface.
In use, the solution from the cartridge is supplied to the rear
surface of the vibratable member having the large opening. As the
vibratable member is vibrated, the apertures emit the solution from
the small openings on the front surface as an aerosolized spray.
The user then simply inhales the aerosolized spray to supply the
chemical to the patient's lungs.
Alternative Embodiments
The invention further provides exemplary methods and apparatus for
aerosolizing a solution. In one exemplary embodiment, an apparatus
comprises a cartridge having a first chamber, a second chamber, and
a moveable divider between the first and the second chambers. An
exit opening is included in the cartridge and is in communication
with the second chamber. A liquid is disposed in the first chamber,
and a substance that is in a dry state is in the second chamber.
The apparatus further includes a piston that is translatable within
the cartridge to transfer the liquid from the first chamber and
into the second chamber to form a solution. An aerosol generator is
further provided and is disposed near the exit opening to receive
the solution from the cartridge and produce an aerosolized
solution. In this way, the substance may be maintained in a dry
state as with other embodiments until ready for aerosolization. To
form the solution, the piston is moved within the cartridge to
force the liquid from the first chamber and into the second
chamber. Further translation of the piston forces the recently
formed solution from the second chamber and onto the aerosol
generator where the solution is aerosolized.
In one particular aspect, the divider has a home position where a
seal is formed between the divider and the cartridge. In this way,
the liquid may be held in the first chamber until the piston is
translated. Preferably, the cartridge includes at least one groove
that is disposed at least part way between the first and second
chambers. In this way, as the piston is moved within the first
chamber, the liquid (which is generally incompressible) moves the
divider toward the second chamber to allow the liquid to pass
around the divider and into the second chamber. The groove
preferably terminates at the second chamber so that when the piston
moves the divider into the second chamber, a seal is formed between
the cartridge and the divider to force the solution from the second
chamber and out the exit opening.
In some cases, it may be desirable to draw the solution back into
the first chamber to facilitate mixing. This can be accomplished by
withdrawing the piston back through the first chamber to create a
vacuum in the first chamber. To dispense the solution, the piston
is translated back through the first and second chambers as
previously described.
In one particular aspect, a filter is disposed across the exit
opening to prevent larger particles from exiting the chamber and
clogging the aerosol generator. In another aspect, the apparatus
includes a motor to translate the piston. In this way, an
aerosolized solution may be supplied to the patient simply by
actuating the motor.
In yet another aspect of the present invention, the present
invention is also directed to a device for aerosolizing a liquid
having a chamber with a deformable wall. The wall moves between
collapsed and expanded positions to accommodate varying volumes of
fluid. The chamber moves to the expanded position in response to
fluid being delivered to the chamber and collapses as fluid is
expelled. The chamber contains a volume of 10-1000 .mu.L, more
preferably 10-750 .mu.L, and most preferably 10-500 .mu.L, while
preferably maintaining the fluid pressure of less than 15 psi in
the chamber. A container, which holds enough liquid to fill the
chamber at least three times, delivers fluid to the chamber. The
wall may be attached to the vibrating structure or may be replaced
with the container.
The device preferably has a valve positioned between the container
and the chamber to isolate the chamber from the container. The
valve may be formed with the wall so that the valve forms part of
the wall. The valve is preferably positioned less than 1 mm from
the back side of the vibrating structure so that the chamber has a
low volume when collapsed. The chamber preferably has a volume of
less than 5 .mu.L and more preferably less than 2 .mu.L when
collapsed. The valve is preferably positioned adjacent to the holes
in the vibrating structure.
These and other aspects and advantages of the invention are
described in the following description, claims and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates a partial cutaway view of an exemplary apparatus
having an aerosol generator for aerosolizing liquids according to
the invention.
FIG. 2 is a schematic diagram of an inhalation flow sensor for
detecting when a patient begins to inhale from an aerosolizing
apparatus according to the invention.
FIG. 3 is a cross-sectional side view of an aerosol generator of
the aerosolizing apparatus of FIG. 1.
FIGS. 4-9 illustrate cross-sectional side views of a container and
a piston pump used in the apparatus of FIG. 1 to deliver a
predetermined volume of liquid to the aerosol generator. The views
illustrated in FIGS. 4-9 show various states of the piston pump
when metering and transferring liquids from the container to the
aerosol generator.
FIG. 10 is a schematic view of an aerosolizing system having a
removable cartridge holding a substance that is in a solid state
according to the invention.
FIG. 11 illustrates the aerosolizing system of FIG. 10 having the
cartridge removed for cleaning of the aerosol generator according
to the invention.
FIG. 12 is a cross sectional side view of an alternative apparatus
for aerosolizing a solution according to the invention.
FIG. 13 illustrates a dual chamber drug cartridge and an aerosol
generator of the apparatus of FIG. 12.
FIGS. 14-17 illustrate the drug cartridge of FIG. 13 in various
states of operation to dispense a solution onto the aerosol
generator according to the invention.
FIG. 18 illustrates the apparatus of FIG. 1 with an alternative
cartridge to deliver liquids to the aerosol generator according to
the invention.
FIG. 19 illustrates the cartridge and aerosol generator of FIG.
18.
FIG. 20 is a cross-sectional view of the cartridge of FIG. 19.
FIG. 21 is a more detailed view of the cartridge of FIG. 19.
FIG. 22 is a cross-sectional side view of a dispensing system
having a drug cartridge and a piston pump according to the
invention.
FIG. 23 shows a chamber having a deformable wall in a collapsed
condition.
FIG. 24 shows the chamber of FIG. 23 expanded to hold fluid.
FIG. 25 shows another deformable wall for the chamber.
FIG. 26 shows the wall of FIG. 25 expanded to hold fluid.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
The invention provides exemplary systems, apparatus and methods for
reconstituting a solid substance that is in a dry state with
liquid, such as water, to form a solution and for transporting the
solution to an aerosol generator for subsequent atomization. In one
exemplary embodiment, the system comprises a liquid dispenser, a
cartridge containing the substance that is in the dry state, and an
aerosol generator. In use, the cartridge is coupled to an outlet of
the dispenser. The user then actuates the liquid dispenser so that
liquid is dispensed from the dispenser and enters into the
cartridge. As the liquid flows through the cartridge, the dry
substance is dissolved into the liquid and exits the cartridge as a
solution. Preferably, the cartridge is replaced and disposed after
each use. In a preferred embodiment, an outlet end of the cartridge
is positioned near the aerosol generator so that the solution
disposed on the aerosol generator is readily available for
atomization.
In one alternative, a two step process is employed to reconstitute
the solution and deliver the solution to the aerosol generator.
First, a portion of a unit volume of liquid, such as one-half a
unit volume, is supplied to the cartridge when the liquid dispenser
is operated. The user then waits a predetermined amount of time,
such as about 10 seconds, and again operates the liquid dispenser
to deliver sufficient liquid into the cartridge to force a unit
volume of solution from the cartridge an onto the aerosol
generator. In this way, a period of time is provided to allow more
of the substance to dissolve in the liquid.
In another aspect of the invention, exemplary systems and methods
are provided for metering relatively small volumes of liquid
directly from a container and for delivering the metered volume to
an atomizer. The systems and methods are configured to precisely
meter and deliver relatively small volumes of liquid, typically in
the range from about 10 .mu.L to about 100 .mu.L. When delivering
volumes in the range from about 10 .mu.L to 50 .mu.L, the invention
preferably employs the use of a piston pump that is connected to a
canister as described in greater detail hereinafter. For volumes in
the range from about 50 .mu.L to about 100 .mu.L, a pharmaceutical
pump is preferably employed, such as metered dose S4 pump,
commercially available from Somova S. p.A. Milano, Italy.
Optionally, such pharmaceutical pumps may also contain a
pharmaceutical medicament which may be delivered directly to the
aerosol generator. As one example, the pharmaceutical medicament
may comprise a suspension of colica steroid for treatment of
asthma.
Another feature of the liquid dispensers of the invention is that
they are configured to prevent or substantially reduce the
possibility of contamination. In this way, each subsequent dosage
delivered by the liquid dispenser is not contaminated when
delivered to the atomizer. Referring now to FIG. 1, an exemplary
apparatus 10 for atomizing a liquid will be described. Apparatus 10
comprises a housing 12 which is configured to hold the various
components of apparatus 10. Housing 12 is preferably constructed to
be lightweight and pocket-sized, typically being molded of a
plastic material. Housing 12 is divided into two separable
portions. A first portion 14 includes an electronics compartment
and a second portion 16 includes a liquid holding compartment for
holding a canister 18, an aerosol generator 22, and a mouthpiece 20
through which the atomized liquids are dispensed to the patient.
Conveniently, second portion can be separated from first portion 14
by sliding a knob 23. Optionally, second portion 16 having the
liquid holding component may be disposed following separation from
first portion 14. Second portion 16 may be disposed along with
canister 18, or canister 18 may be disposed separately.
Apparatus 10 further includes an inhalation flow sensor 24 which
detects the inhalation flow produced by the patient when inhaling
from mouthpiece 22. Upon detection of the inhalation, sensor 24
sends an electrical signal to an electronic circuit (not shown)
which in turn sends an alternating voltage to vibrate a
piezoelectric member 26 of aerosol generator 22 to aerosolize a
liquid. Sensor 24 preferably comprises a flexure foil and an
electro-optical sensor. The flexible foil deflects in response to
the inhalation airflow produced when a patient inhales from
mouthpiece 20. The optical sensor is configured to detect
deflection of the flexible foil so that a signal may be produced to
vibrate piezoelectric member 26.
Referring now to FIG. 2, a schematic diagram of an inhalation flow
sensor 24 will be described. Flow sensor 24 comprises a flexible
foil 28 having an extension 30. Inhalation flow sensor 24 further
includes an optical sensor 32 which includes a light emitting diode
(LED) 34 and a light sensitive transistor 36 placed in apposition
to LED 34 so that LED 34 continuously transmits a light beam 38 to
transistor 36. When the patient inhales, the inhalation airflow
causes flexible foil 28 to deflect and move extension 30 downward
until it crosses light beam 38 and causes an optical interruption
that is detected by transistor 36. Transistor 36 then sends a
signal to trigger activation of an aerosol generator to produce an
aerosol.
By configuring inhalation flow sensor 24 in this manner, aerosol
generator 22 is actuated only in response to the detection of an
inhalation airflow produced by a patient. In this way, the patient
may be administered a single dose using either a single inhalation
or multiple inhalations. Preferably, inhalation flow sensor 24 is
triggered at an inhalation flow rate of at least 15 liters per
minute. However, it will be appreciated that sensor 24 may be
constructed to trigger at either lower or higher flow rates.
Adjustment of the actuation point may be accomplished by altering
the flexible stiffness of foil 28, by selecting different materials
for constructing foil 28 or by changing the thickness of foil
28.
Alternatively, the inhalation flow sensor may be constructed from a
piezoelectric film component. The piezoelectric film component
produces an electrical signal when it deflects. The magnitude of
the electrical signal is proportional to the magnitude of
deflection. In this way, the electrical signal that is produced by
the piezoelectric film component can be used to detect the
magnitude of the inhalation flow. In this manner, the output of the
aerosol generator may be adjusted in proportion to the inhalation
airflow. Such a proportional output from the aerosol generator is
particularly advantageous in that it prevents the coalescence of
particles and controls the aerosol production according to the
inhalation flow. Control of the aerosol output may be adjusted by
turning the aerosol generator on and off sequentially. The ratio
between the on time and the off time, generally defined as the duty
cycle, affects the net flow. An exemplary piezoelectric film
component with such characteristics is commercially available from
ATO Autochem Sensors, Inc., Valley Forge, Pa.
Referring back to FIG. 1, the electronic circuit (not shown) within
first portion 14 includes electrical components to detect the
presence of liquid on aerosol generator 22 and to send a signal to
the user indicating that all of the liquid has been aerosolized. In
this way, the user will know if additional inhalations will be
required in order to receive the prescribed amount of medicament.
The sensing circuit preferably comprises a voltage sensing circuit
(not shown) which detects the voltage across piezoelectric element
member 26. Since the voltage across piezoelectric member 26 is
proportionally related to the amount of liquid in surface tension
contact with an aperture plate 40 (see FIG. 3) of aerosol generator
22, it can be determined, based on the voltage, whether any liquid
is left remaining. For example, when aerosolization is initiated,
the voltage is high. At the end of aerosolization, the voltage is
low, thereby indicating that the aerosolization process is near
completion. Preferably, the sensing circuit is configured to be
triggered when about 95% of the liquid has been aerosolized. When
triggered, the sensing circuit turns on a light emitting diode
(LED) 42 indicating that the prescribed dosage has been
delivered.
Referring now to FIG. 3, construction of aerosol generator 22 will
be described in greater detail. As previously described, aerosol
generator 22 includes a vibratable aperture plate 40 and annular
piezoelectric member 26. Aerosol generator 22 further comprises a
cup-shaped member 44 to which piezoelectric member 26 and aperture
plate 40 are attached as shown. Cup-shaped member 44 includes a
circular hole 46 over which aperture plate 40 is disposed. Wires
(not shown) connect piezoelectric member 26 to the electrical
circuitry within portion 14 (see FIG. 1) which in turn is employed
to vibrate piezoelectric member 26.
Cup-shaped member 44 is preferably constructed of a low damping
metal, such as aluminum. Aperture plate 40 is disposed over hole 46
such that a rear surface 48 of aperture plate 40 is disposed to
receive liquid from canister 18 (see FIG. 1). Although not shown,
aperture plate 40 includes a plurality of tapered apertures which
taper from rear surface 48 to a front surface 50. Exemplary
aperture plates which may be used with the invention include those
described the '740 patent, the '550 patent, and the '637 patent,
previously incorporated by reference.
Aperture plate 40 is preferably constructed of a material that may
be produced by a metal electroforming process. As an example,
aperture plate 40 may be electroformed from palladium or a
palladium alloy, such as palladium cobalt or palladium nickel.
Aperture plate 40 may further be gold electroplated to enhance its
corrosion resistance. Alternatively, aperture plate 40 may be
constructed of nickel, a nickel-gold alloy, or a combination of
nickel and nickel-gold alloy arranged such that the nickel-gold
alloy covers the external surfaces of the aperture plate. The
nickel-gold alloy may be formed using a gold electroplating process
followed by diffusion at an elevated temperature as described
generally in Van Den Belt, TGM, "The diffusion of platinum and gold
in nickel measured by Rutherford Fact Scattering Spectrometry",
Thin Solid Film, 109 (1983), pp. 1-10. The complete disclosure of
this reference is incorporated herein by reference. A small amount
of manganese may also be introduced to the nickel during the
electroforming process so that the nickel can be heat treated at an
elevated temperature as described generally in U.S. Pat. No.
4,108,740, incorporated herein by reference. The gold-nickel alloy
is particularly useful in protecting the nickel components, and
particularly the electroformed nickel components, from corrosion
caused by plating porosity. The diffusion process may be useful for
other applications which require corrosion protection for nickel
components, and particularly nickel electroformed components, such
as, for example, inkjet aperture plates, other spray nozzle plates,
and the like.
As another alternative, corrosion resistance of the aperture plate
may be enhanced by constructing the aperture plate of a composite
electroformed structure having two layers, with the first
electroformed layer comprising nickel and the second electroformed
layer comprising gold. The thickness of the gold in the composite
in preferably at least two microns, and more preferably, at least
five microns. Alternatively, the second layer may be electroformed
from palladium or another corrosive-resistant metal. The external
surfaces of the aperture plate may also be coated with a material
that prevents bacteria growth, such as polymyxin or silver.
Optionally, other coatings that enhance wetability may be applied
to the aperture plate.
In one embodiment, the aperture plate is protected from corrosive
liquids by coating the aperture plate with agents that form a
covalent bond with the solid surface via a chemical linking moiety.
Such agents are preferred because the are typically biocompatable
with acidic pharmaceutical liquids. The agent may be photoreactive,
i.e. activated when subjected to light or may be activated when
subjected to moisture or to any other means of energy. Further, the
agent may have various surface properties, e.g. hydrophobic,
hydrophilic, electrically conductive or non-conductive. Still
further, more than one agent may be formed on top of each other.
Types of coatings that may be included on the aperture plate are
described in U.S. Pat. Nos. 4,979,959; 4,722,906; 4,826,759;
4,973,493; 5,002,582; 5,073,484; 5,217,492; 5,258,041; 5,263,992;
5,414,075; 5,512,329; 5,714,360; 5,512,474; 5,563,056; 5,637,460;
5,654,460; 5,654,162; 5,707,818; 5,714,551; and 5,744,515. The
complete disclosures of all these patents are herein incorporated
by reference.
Cup-shaped member 44 is disposed within a housing 52 which prevents
liquids from coming into contact with piezoelectric member 26 and
with cup-shaped member 44. Cup-shaped member 44 is suspended within
housing 52 by two elastic rings 54 and 56. Ring 54 is positioned
between housing 52 and the circumference of cupshaped member 44.
Ring 56 is positioned between the inner diameter of piezoelectric
member 26 and a shield member 58. Such an arrangement provides a
hermetic seal that prevents the contact of liquids with the
piezoelectric member 26 without suppressing the vibratory motion of
cup-shaped member 44.
Referring back now to FIG. 1, aerosol generator 22 is axially
aligned with mouthpiece 20 so that when piezoelectric member 26 is
vibrated, liquid droplets are ejected through mouthpiece 20 and are
available for inhalation by the patient. As previously described,
disposed within second portion 16 is a canister 18 which holds the
liquid medicament to be atomized by aerosol generator 22. Canister
18 is integrally attached to a mechanical pump 60 which is
configured to dispense a unit volume of liquid through a nozzle 62
to aerosol generator 22. Pump 60 is actuated by pressing a knob 64
which pushes canister 18 downward to generate the pumping action as
described in greater detail hereinafter. Pressing on knob 64 also
puts pressure on an electrical microswitch 66 within second portion
16. When actuated, microswitch 66 sends a signal to the electrical
circuit within first portion 14 causing a light emitting diode
(LED) (not shown) to blink indicating that apparatus 10 is ready
for use. When the patient begins to inhale, the inhalation is
sensed causing actuation of the aerosol generator.
As illustrated in FIG. 3, pump 60 delivers a unit volume of liquid
68 (shown in phantom line) to rear surface 48 of aperture plate 40.
The delivered volume 68 adheres to aperture plate 40 by
solid/liquid surface interaction and by surface tension forces
until patient inhalation is sensed. At that point, piezoelectric
member 26 is actuated to eject liquid droplets from front surface
50 where they are inhaled by the patient. By providing the
delivered volume 60 in a unit volume amount, a precise dose of
liquid medicament may be atomized and delivered to the lungs of the
patient. Although canister 18 of FIG. 1 is shown as being
configured to directly deliver the dispensed liquid to the aperture
plate, pump 60 may alternatively be configured to receive a
cartridge containing a chemical in a dry state as described in
greater detail hereinafter.
Referring now to FIGS. 4-10, a schematic representation of a
canister 138 and a piston pump 140 will be described to illustrate
an exemplary method for dispensing a unit volume of a liquid
medicament to an aperture plate, such as aperture plate 40 of
apparatus 10 (see FIGS. 1 and 3). Canister 138 comprises a housing
142 having an open end 144 about which a cap 146 is placed.
Disposed against open end 144 is a washer 148 which provides a seal
to prevent liquids from escaping from housing 142. On top of washer
148 is a cylindrical member 150. Cap 146 securely holds cylindrical
member 150 and washer 148 to housing 142. Cylindrical member 150
includes a cylindrical opening 151 which allows liquids to enter
from canister 138. Cylindrical member 150 in combination with
washer 148 also serve to securely position a holding member 152
about which a compression spring 154 is disposed.
Piston pump 140 comprises a piston member 156, cylindrical member
150, a valve seat 158 and compression spring 154. Piston member 156
has a frontal end 156A and a distal end 156B, with frontal end 156A
providing the piston action and distal end 156B providing the valve
action.
Piston pump 140 is configured such that every time valve seat 158
is depressed toward canister 138 and then released, a unit volume
of liquid is dispensed through a tapered opening 161 in valve seat
158. Valve seat 158 includes a valve seat shoulder 158A which is
pressed to move valve seat inwardly, causing valve seat 158 to
engage with distal end 156B to close tapered opening 161.
As shown in FIG. 5, as piston member 156 is further depressed into
cylindrical member 150, spring 154 is compressed and a metering
chamber 168 begins to form between frontal end 156A and cylindrical
member 150. Frontal end 156A and distal end 156B are preferably
constructed from a soft elastic material which provides a hermetic
seal with cylindrical member 150 and valve seat 158, respectively.
Due to the seal between frontal end 156A and cylindrical member
150, a vacuum is created within metering chamber 168 upon
depression of piston member 156.
As piston member 156 is further moved into cylindrical member 150
(see FIG. 6), spring 154 is further compressed and frontal end 156A
moves past cylindrical opening 151 so that a gap is provided
between frontal end 156A and cylindrical member 150. As frontal end
156A passes the edge of cylindrical member 150, liquid from
canister 138 is drawn into cylindrical member 150 by the vacuum
that was created within metering chamber 168. In FIG. 6, piston
member 156 is in the filling position.
At the end of inward travel, the user releases the pressure on
valve seat 158, allowing spring 154 to push piston member 156 back
toward its starting position. As illustrated in FIG. 7, upon the
return travel of piston member 156 to the starting position,
frontal end 156A again engages cylindrical member 150 and forms a
seal between the two surfaces to prevent any liquid within metering
chamber 168 from flowing back into canister 138.
Since the liquid within metering chamber 168 is generally
incompressible, as spring 154 pushes on piston member 156, the
liquid within metering chamber 168 forces valve seat 158 to slide
distally over piston member 156. In so doing, the liquid within
metering chamber 168 is allowed to escape from the metering chamber
through tapered opening 161 of valve seat 158 as illustrated in
FIG. 8.
As illustrated in FIGS. 7-9, liquid from metering chamber 168 is
dispensed from tapered opening 161 as frontal end 156A travels
length L. As frontal end 156A passes through length L, it is in
contact with cylindrical member 150. In this way, the liquid within
metering chamber 168 is forced out of tapered opening 161 during
this length of travel. After passing through Length L, frontal end
156A passes out of sealing relationship with cylindrical member 150
so that no further liquid is dispensed from tapered opening 161.
Hence, the amount of liquid dispensed is proportional to the
diameter of cylindrical member 150 over length L. As such, piston
pump 140 may be designed to dispense a known volume of liquid each
time piston member 156 travels from the starting position to the
filling position and then back to the starting position. Since
piston member 156 must be fully depressed to the filling position
in order to create a gap between frontal end 156A and cylindrical
member 150, a way is provided to ensure that partial volumes can
not be dispensed.
As shown in FIG. 9, valve seat 158 includes a shoulder 170 which
engages a stop 172 on cylindrical member 150 to stop distal
movement of valve seat 158 relative to cylindrical member 150. At
this point, piston pump 140 is at an ending dispensing position
which corresponds to the starting position as initially illustrated
in FIG. 4. In this position, spring 154 forces distal end 156B of
piston member 156 into tapered opening 161 to provide a seal and
prevent contaminants from entering into piston 140.
Valve seat 158 is preferably coated with a material that inhibits
proliferation of bacteria. Such coatings can include, for example,
coatings having a positive electric charge, such as polymyxin,
polyethylinimin, silver, or the like.
The invention further provides a convenient way to store chemical
substances in the solid or dry state and then to dissolve the
chemical substance with liquid from the canister to form a
solution. In this way, chemical substances that are otherwise
susceptible to degradation can be stored in the dry state so that
the shelf life of the product is extended. An exemplary embodiment
of a cartridge 180 for storing such chemical substances that are in
the dry state is illustrated in FIG. 10. For convenience of
illustration, cartridge 180 will be described in connection with
piston pump 140 and canister 138, which in turn may be coupled to
an aerosolization apparatus, such as apparatus 10, to aerosolize a
medicament as previously described. Cartridge 180 comprises a
cylindrical container 182 having an inlet opening 184 and outlet
opening 186. Inlet opening 182 is sized to be coupled to piston
pump 140 as shown. Disposed within container 182 is a first filter
188 and a second filter 190. Filter 188 is disposed near inlet
opening 184 and second filter 190 is disposed near outlet opening
186. A chemical substance 192 which is in a dry state is disposed
between filters 188 and 190. Chemical substance 192 is preferably
held within a support structure to increase the rate in which the
chemical substance is dissolved.
The support structure may be constructed of a variety of materials
which are provided to increase the rate in which the chemical
substance is dissolved. For example, the support structure may
comprise an open cell material such as a polytetrafluoroethylene
(PTFE) matrix material commercially available from Porex
Technologies, Farburn, Ga. Preferably, such an open cell material
has a pore size in the range from about 7 .mu.m to about 500 .mu.m,
and more preferably about 250 .mu.m. Alternatively, various other
plastic materials may be used to construct the open cell matrix,
including olyethylene (HDPE), ultra-high molecular weight
polyethylene (UHMW), polypropylene (PP), polyvinylidene fluoride
(PVDF), nylon 6 (N6), polyethersulfone (PES), ethyl vinyl acetate
(EVA), and the like. Alternatively, the support structure may be
constructed of a woven synthetic material, a metal screen, a stack
of solid glass or plastic beads, and the like.
An exemplary method for placing chemical substance 192 into
container 182 is by filling container 182 with the chemical
substance while the chemical substance is in a liquid state and
then lyophilizing the substance to a dry state while the substance
within the cartridge. In this way, filling of cartridge 180 with a
chemical substance may be precisely and repeatedly controlled.
However, it will be appreciated that the chemical substance may be
placed into cartridge 180 when in the solid state.
Lyophilization is one exemplary process because it will tend to
reduce the rate of various physical and chemical degradation
pathways. If the substance comprises a protein or peptide, both the
lyophilization cycle (and resulting moisture content) and product
formulation can be optimized during product development to
stabilize the protein before freezing, drying and for long term
storage. See Freeze Drying of Proteins, M. J. Pikal, BioPharm. 3,
18-26 (1990); Moisture Induced Aggregation of Lyophilized Proteins
in the Solid State, W. R. Liu, R. Langer, A. M. Klibanov, Biotech.
Bioeng. 37, 177-184 (1991); Freeze Drying of Proteins. II, M. J.
Pikal, BioPharm. 3, 26-30 (1990); Dehydration Induced
Conformational Transitions in Proteins and Their Inhibition by
Stabilizers, S. J. Prestrelski, N. Tedeschi, S. Arakawa, and J. F.
Carpenter, Biophys. J. 65, 661-671 (1993); and Separation of
Freezing and Drying Induced Denaturation of Lyophilized Proteins
Using Stress-Specific Stabilization, J. F. Carpenter, S. J.
Prestrelski, and T. Arakawa, Arch. Biochem. Biphys. 303, 456-464
(1993), the complete disclosures of which are herein incorporated
by reference. Adjustment of the formulation pH and/or addition of a
wide variety of additives including sugars, polysaccharides,
polyoles, amino-acids, methylamines, certain salts, as well as
other additives, have been shown to stabilize protein towards
lyophilization.
As an example, which is not meant to be limiting, a cartridge was
packed with small glass beads having a diameter of approximately
0.5 mm. The cartridge was filed with a solution of lysozyme at a
concentration of 10 mg/ml. To enhance its stability, the solution
was combined with a form of sugar and with a buffer solution. The
buffer solution was sodium citrate, and the sugar was mannitol. A
twin 20 surfactant was also added to the solution. The solution was
then lyophilized in the cartridge.
The lyophilized substance may optionally contain a solubility
enhancer, such as a surfactant as described in Journal of
Pharmaceutical Science Technology which is J.Pharmsei. Technology,
48; 30-37 (1994) the disclosure of which is herein incorporated by
reference. To assist in protecting the chemical substance from
destructive reactions while in the dry state, various sugars may be
added as described in Crowe, et al., "Stabilization of Dry
Phospholipid Bilayer and Proteins by Sugars", Bichem. J. 242: 1-10
(1987), and Carpenter, et al. "Stabilization of Phosphofructokinase
with Sugars Drying Freeze-Drying", Biochemica. et Biophysica Acta
923: 109-115 (1987), the disclosures of which are herein
incorporated by reference.
In use, cartridge 180 is coupled to piston pump 140 and piston pump
140 is operated as previously described to dispense a known volume
of liquid into cartridge 180. The supplied liquid flows through
chemical substance 192 and chemical substance 192 dissolves into
the liquid and flows out of outlet opening 186 as a liquid solution
194. Outlet opening 186 is spaced apart from an aperture plate 196
of an aerosol generator 198 so that liquid solution 198 will be
deposited on aperture plate 196 as shown. Aerosol generator 198
further includes a cup shaped number 200 and a piezoelectric member
202 and operates in a manner similar to the aerosol generator 22 as
previously described. Hence, when aerosol generator 198 is
operated, liquid solution 194 is ejected from aperture plate 196 in
droplet form as shown.
One important feature of the invention is that cartridge 180 is
removable from piston pump 140 so that cartridge 180 may be
discarded following each use. As illustrated in FIG. 11, after
cartridge 180 has been removed, the user may optionally actuate
piston pump 140 to again deliver a volume of liquid 204 directly to
aperture plate 96. Aerosol generator 198 is then operated so that,
similar to an ultrasonic cleaner, the vibratory action removes any
residual solution from aperture plate 196. Liquids that may be held
within canister 138 to form the solution and to clean aperture
plate 196 include sterile water, a mixture of water with ethanol or
other disinfectant, and the like.
In summary, the invention provides a portable aerosolizing
apparatus that is able to store a chemical substance in the dry
state, and to reconstitute the chemical substance with liquid to
form a solution just prior to administration. The invention further
provides techniques for aerosolizing the solution and for cleaning
the aerosol generator. Also, it will be appreciated that the
aerosolization apparatus as described herein may be used to
aerosolize a liquid medicament that is not stored within a
cartridge so that the liquid medicament is passed directly from the
piston pump and on to the aperture plate for aerosolization.
Apparatus 10 may optionally be configured to warn the user when
cleaning is needed. Such a feature is best accomplished by
providing a processor within second portion 14 which is programmed
to include an expected amount of time required to aerosolize a dose
received from canister 18. If the expected amount of time exceeded
before the entire dose is aerosolized, it may be assumed that the
apertures in the aperture plate are clogged, thereby requiring
cleaning to clear the apertures. In such an event, the processor
sends a signal to an LED on apparatus 10 indicating that cleaning
is needed.
To determine whether all of the liquid has been aerosolized in the
expected time period, the processor records the amount of time that
the aerosol generator is actuated. When the aerosol generator has
been actuated for the expected time, the voltage sensing circuit is
actuated to detect whether any liquid remains on the aperture plate
as previously described.
Referring now to FIG. 12, an alternative embodiment of an apparatus
300 for atomizing a liquid solution will be described. Apparatus
300 includes a housing 302 that is divided into two separable
portions similar to the embodiment of FIG. 1. A first portion 304
includes various electronics and a second portion 306 includes a
liquid holding compartment. An aerosol generator 308 which is
similar to aerosol generator 22 of FIG. 1 is disposed in second
portion 306 to aerosolize a solution where it will be available for
inhalation through a mouthpiece 310. Conveniently, aerosol
generator 308 includes a lip 312 to catch the solution and maintain
it in contact with the aerosol generator 308 until aerosolized.
Disposed above aerosol generator 308 is a drug cartridge 314. As
will be described in greater detail hereinafter, cartridge 314 is
employed to produce a solution which is delivered to aerosol
generator 308 for aerosolization.
Coupled to cartridge 314 is a lead screw 316. In turn, lead screw
316 is coupled to a micro-coreless DC motor 318. When motor 318 is
actuated, it causes a shaft 320 to rotate. This rotational motion
is converted to linear motion by lead screw 316 to translate a
piston 322 within cartridge 314 as described in greater detail
hereinafter. Motor 318 is actuated by appropriate electronics held
in first portion 304. Further, a power source, such as a battery,
is also held within first portion 304 to supply power to motor 318.
Aerosol generator 38 is operated in a manner essentially identical
to that previously described in connection with the apparatus of
FIG. 1.
Referring now to FIG. 13, construction of cartridge 314 will be
described in greater detail. Piston 322 includes a docking knob 324
which mates with a connector 326 of lead screw 316. Docking knob
324 and connector 326 are configured to facilitate easy coupling
and uncoupling. Typically, motor 318 and lead screw 316 are
securely coupled to housing 308 (see FIG. 12), while cartridge 314
is configured to be removable from housing 302. In this way, each
time a new drug cartridge is required, it may be easily inserted
into apparatus 300 and coupled with lead screw 316.
Lead screw 316 is configured such that when motor 318 causes shaft
320 to rotate in a clockwise direction, lead screw 316 is moved
downward. Alternatively, when motor 318 is reversed, lead screw 316
is moved upward. In this way, piston 322 may be translated back and
forth within cartridge 314. Motor 318 is preferably calibrated such
that piston 322 can be moved to selected positions within cartridge
314 as described in greater detail hereinafter.
Cartridge 314 includes a first chamber 328 and a second chamber
330. Although not shown for convenience of illustration, first
chamber 328 is filled with a liquid and second chamber 330 includes
a substance that is in a dry state. Such a substance preferably
comprises a lyophilized drug, although other substances may be
employed similar to the embodiment of FIG. 1. Separating first
chamber 328 and second chamber 330 is a divider 332. As shown in
FIG. 13, divider 332 is in a home position which forms a seal
between divider 332 and cartridge 314 so that the liquid is
maintained within first chamber 328 until divider 332 is moved from
its home position as described hereinafter.
Cartridge 314 includes an exit opening 333 which is disposed in
close proximity to aerosol generator 308. Once the solution is
formed within cartridge 314, it is dispensed through exit opening
333 and on to aerosol generator 308 where it will be aerosolized
for delivery to the patient. Disposed across exit opening 333 is a
filter 334 which serves to prevent larger drug particles from being
flushed out onto aerosol generator 308, thus causing potential
clogging of the apertures within aerosol generator 308.
Referring now to FIGS. 14-17, operation of cartridge 314 to produce
a solution which is delivered to aerosol generator 308 will be
described. Cartridge 314 is constructed in a manner similar to the
drug cartridge described in U.S. Pat. No. 4,226,236, the complete
disclosure of which is herein incorporated by reference. As shown
in FIG. 14, cartridge 314 is in the home position where divider 332
maintains the liquid within first chamber 328. When in the home
position, cartridge 314 may be inserted into apparatus 300 and
coupled to lead screw 316 (see FIG. 13). When ready to deliver an
aerosolized solution to a patient, motor 318 (see FIG. 13) is
actuated to cause lead screw 316 to translate piston 322 within
cartridge 314 as illustrated in FIG. 15. As piston 322 is
translated within cartridge 314, it begins to move through first
chamber 328. Since the liquid is generally incompressible, the
liquid will force divider 332 to move in the direction of second
chamber 330. Formed in the walls of cartridge 314 are one or more
grooves 336 which are placed in communication with first chamber
328 as divider 332 moves away from its home position. As such, the
liquid within first chamber 328 is forced into chamber 330 as
illustrated by the arrows. Once the liquid is able to flow around
divider 332, the pressure acting against it is relieved so that it
remains in the position generally shown in FIG. 15. As the liquid
enters into second chamber 330, the lyophilized drug is dissolved
into the liquid to form a solution.
As illustrated in FIG. 16, piston 322 is translated until it
engages divider 332. At this point, all of the liquid has been
transferred from first chamber 328 into second chamber 330. At this
point, it may optionally be desired to mix the solution that has
just been formed within second chamber 330. This may be
accomplished by translating piston 322 backward toward the position
illustrated in FIG. 15. In so doing, a vacuum is created within
first chamber 328 to draw the solution from second chamber 330 into
first chamber 328. As the solution flows through grooves 336, the
solution is agitated, causing mixing. Piston 322 may then be
translated back to the position shown in FIG. 16 to move the liquid
back into second chamber 330. This process may be repeated as many
times as needed until sufficient mixing has occurred.
After proper mixing, the solution is ready to be dispensed onto the
aerosol generator. To do so, piston 332 is moved through second
chamber 330 as illustrated in FIG. 17. In turn, divider 332 is
pushed against filter 334 to completely close second chamber 330
and force all of the liquid out exit opening 333.
One particular advantage of cartridge 314 is that a precise volume
of drug is dispensed onto aerosol generator 308 to ensure that the
patient will receive the proper dosage. Further, by maintaining the
drug in the dry state, the shelf life may be increased as
previously described.
Following dispensing of the solution, cartridge 314 may be removed
and replaced with another replacement drug cartridge. Optionally, a
cleaning cartridge may be inserted into apparatus 300 which
includes a cleaning solution. This cleaning solution is dispensed
onto aerosol generator 308 upon operation of motor 318. Aerosol
generator 308 may then be operated to clean its apertures using the
cleaning solution.
Referring now to FIG. 18, an alternative apparatus 400 for
atomizing a liquid will be described. Apparatus 400 is essentially
identical to apparatus 10 except that canister 18 has been replaced
with a continuous feed cartridge 402. Cartridge 402 is configured
to continuously feed liquid to aerosol generator 22 on demand so
that enough liquid will always be available each time aerosol
generator 22 is actuated. Cartridge 402 also ensures that excessive
liquid will not be supplied, i.e. it will supply only as much
liquid as is atomized. Cartridge 402 is constructed similar to the
cartridges described in co-pending U.S. patent application Ser. No.
08/471,311, filed Apr. 5, 1995, the complete disclosure of which is
herein incorporated by reference.
As illustrated in FIGS. 19-21, cartridge 402 comprises a liquid
reservoir 404 and a face 406 which is adjacent the aperture plate
of aerosol generator 22 to supply liquid from liquid reservoir 404
to the aperture plate. A capillary pathway 408 extends between
reservoir 404 and face 406 to supply liquid to face 406 by
capillary action. In order to overcome the vacuum that is produced
in reservoir 404, a venting channel 410 is in communication with
pathway 408. In this way, air is able to enter into reservoir 404
to reduce the vacuum and allow additional liquid to be transferred
from reservoir 404.
In another embodiment, a drug cartridge may be coupled to a piston
pump to form a dispensing system that is used to supply a formation
to an aerosol generator. For example, as shown in FIG. 22, a
dispensing system 430 comprises a cartridge 432 and a piston pump
434. Cartridge 432 is patterned after cartridge 314 of FIG. 14 and
includes a first chamber 436 and a second chamber 438. Disposed in
chamber 436 is a liquid (not shown) and disposed in second chamber
438 is a dried substance 440. A divider 442 separates the chambers.
In use, a plunger 444 is moved through chamber 436 to force divider
442 forward and to allow the liquid to enter chamber 438 and form a
solution.
Piston pump 434 may be constructed similar to pump 138 of FIG. 4.
Pump 434 is operated to dispense a volume of the solution from
chamber 438. Pump 434 may be disposed near an aerosol generator so
that a volume of the solution will be available for atomization. In
this way, known volumes of a solution that was formed from a direct
substance may be provided in an easy and convenient manner.
Referring to FIGS. 23 and 24, another aspect of the invention is
shown wherein the same or similar reference numbers refer to the
same or similar structure. A container 500 delivers fluid to a
chamber 502. The container 500 and chamber 502 are contained within
the housing 12 (FIG. 1) and the aspects of the devices described
above are equally applicable here. Fluid from the container 500
fills the chamber 502 at least three times and more preferably at
least twenty five times.
The chamber 502 is movable between the expanded position of FIG. 24
to the collapsed position of FIG. 23. The chamber 502 expands as
fluid is delivered to the chamber 502 from the container 500 and
collapses as fluid is expelled through holes 504 in a vibrating
structure 506 during operation. The holes 504, which are
exaggerated for clarity, are preferably shaped and sized in the
manner described herein. The vibrating structure 506 is formed by
the cup shaped member 44 and an element 508 having the holes 504.
The element 508 has a domed shape but may be flat, curved or shaped
in any other suitable manner. The vibrating structure 506
preferably vibrates at a frequency of 80-190 kHz, more preferably
about 120-150 kHz, but may also operate at other frequencies. The
vibrating structure 506 is vibrated with any suitable device and is
preferably vibrated with the piezoelectric member 26.
The chamber 502 has a deformable wall 510 which deforms to contain
varying amounts of fluid. The wall 510 preferably bows outward and
away from the vibrating structure 506 when the chamber 502 expands
(FIG. 24). The chamber 502 is also bounded by a back side 503 of
the element 508 so that fluid in the chamber 502 is in contact with
the vibrating structure 506. The chamber 502 preferably contains a
volume of 10-1000 .mu.L, more preferably 10-750 .mu.L and most
preferably about 10-500 .mu.L when fully expanded. The wall 510 may
be somewhat elastic, however, the wall 510 is preferably flexible
enough that the fluid pressure in the chamber 502 is no more than
15 psi, more preferably no more than 10 psi, and most preferably no
more than 5 psi when the chamber 502 is full. Fluid tension
developed at the holes 504 in the vibrating structure hold the
fluid within the chamber 502.
The container 500 has a piston 512 movable within a cylinder 514
containing the fluid. The piston 512 moves within the cylinder 514
to deliver a known quantity of fluid to the chamber 502. The piston
512 may be manually actuated or moved with a motor-driven actuator.
The container 500 may, of course, be any other suitable device or
container 500 including any other device described herein, without
departing from the scope of the invention. Thus, the container 500
may have a number of compartments containing different substances
and may have the valves described above.
A cap 516 is mounted to the container 500. The cap 516 has a needle
518 which pierces a septum 520 on the container 500. The cap 516 is
preferably attached to the container 500 immediately before use so
that the septum 520 is not pierced until just before the container
500 is mounted within the housing 12. The container 500 is then
mounted to a holding element 522 with a threaded connection 524.
The holding element 522 is mounted within the housing 22 in any
suitable manner. The needle 518 defines a fluid path 526 between
the container 500 and the chamber 502.
A valve 528 maintains sterility in the container 500 and prevents
fluid flow from the chamber 502 to the container 500. The valve 528
is preferably a slit-type valve 530 but may, of course, have any
other suitable structure. The valve 528 has upper and lower lips
532, 534 which connect the valve 528 to the wall 510. The valve 528
may also have a threaded connection with the wall 510 which engages
the wall 510 as the container 500 engages the holding element
522.
Use of the device is now described. The cap 516 is attached to the
container 500 so that the needle 518 pierces the septum 520.
Alternatively, the cap 516 may be already attached to the container
500 with the valve 528 maintaining sterility of the container 500
before use. The cap 516 is then rotated into engagement with the
holding element 522 which causes the valve 528 to engage and the
wall 510. The user then selects a desired amount of fluid to be
delivered to the chamber 502. The piston 512 is then moved an
appropriate distance to deliver the desired amount of fluid. As
fluid is delivered from the container 500, the valve 528 opens and
the chamber 502 expands to accommodate the fluid. The chamber 502
may be completely or partially filled. As the chamber 502 is
filled, the fluid pressure preferably remains within the ranges
described above. The piezoelectric member 26 is then used to induce
vibrations in the vibrating structure 506. Vibration of the
vibrating structure 506 forces fluid from the chamber 502 through
the holes 504 and out front side 507 of the vibrating structure
506.
Referring to FIGS. 25 and 26, another aspect of the invention is
shown wherein the same or similar reference numbers refer to the
same or similar structure. The dimensions, operation and use
described above, such as in connection with FIGS. 23 and 24, are
equally applicable here. The container 500 and chamber 502 operate
similar to the container 500 and chamber 502 described above in
that the container 500 delivers fluid to the chamber 502. The
chamber 502 is partially defined by the back side 503 of the
vibrating structure 506 and a deformable wall 510A.
The container 500 differs from the container 500 in that wall 510A
may be replaced periodically and, in the preferred embodiment, is
replaced with each new container 500. A cap 516A has the needle 518
for penetrating the septum 520 on the container 500 as described
above. The cap 516A, needle 518, and wall 510A may be mounted to
the container 500 immediately before mounting the container 500 to
the holding element 522. Alternatively, the wall 510A, needle 518,
cap 516A and container 500 may be packaged together. A valve 530,
preferably a slit-type valve 532, is formed at the end of the
needle 518 to isolate the chamber 502 from the container 500. The
valve 530 defines a fluid outlet 534 positioned less than 1 mm and
more preferably less than 0.5 mm from the back side 503 of the
vibrating structure 506. The valve 530 is preferably positioned
adjacent the holes 504 in the vibrating structure 506.
A spring 534 holds the wall 510A against the vibrating structure
506 to seal the chamber 502. The spring 534 is compressed as the
container 500 is advanced into engagement with the holding element
522. The spring 534 is embedded in the wall 510A and in the cap
516A. The wall 510A is preferably made of a material that has a low
bending stiffness which produces little resistance when expanding.
In this manner, the pressure in the chamber may still be less than
15 psi and more preferably less than 10 psi as mentioned above. The
fluid pressures are maintained at the fluid volumes mentioned
above.
The wall 510A has a portion 536 which conforms to the shape of the
back side 503 of the vibrating structure 522 when collapsed so that
the fluid can be substantially, and preferably completely, removed
from the chamber 502. In this manner, the volume remaining in the
chamber 502 is less than 10 .mu.L, more preferably less than 5
.mu.L and most preferably less than 2 .mu.L. The portion 536 of the
wall 510A conforming to the vibrating structure 522 is preferably
adjacent the holes 504 in the vibrating structure 506.
In another aspect of the invention, the vibrating structure 506 is
able to drop the pressure in the chamber 502 below atmospheric
pressure to help collapse the wall 510, 510A. When the vibrating
structure 522 is vibrated, fluid can be forced through the holes
504 when pressure in the chamber 502 is below atmospheric pressure.
The device shown in FIGS. 25-26 is used in the same manner as the
device of FIGS. 23-24 and the discussion above is incorporated
here.
The invention has now been described in detail, however, it will
appreciated that certain changes and modifications may be made. For
example, although illustrated in the context of delivering liquid
to an aperture plate, the apparatus and methods may be employed to
deliver known quantities of liquid to other types of atomization
devices. Therefore, the scope and content of this invention are not
limited by the foregoing description. Rather the scope and content
are to be defined by the following claims.
* * * * *